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1.
Drugs R D ; 21(4): 361-369, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34435339

RESUMO

Intranasal drug administration is a commonly used route for therapeutic formulations, but there may be challenges associated with a lack of absorption and bioavailability, as well as damage to mucosal tissue. To address these issues, potential absorption enhancers that are generally nonirritating to nasal mucosal tissue have been investigated as excipients in intranasal formulations. Among those studied are alkylsaccharides, which are composed of sugars covalently coupled to at least one alkyl chain. Alkylsaccharides have been shown to be nontoxic and have been used in food products as emulsifiers. In clinical trials, alkylsaccharide excipients have demonstrated substantially increased absorption of therapeutic agents across mucosal membranes and have been shown to be applicable to a wide range of types of molecules and molecular weights. Because they are water and oil soluble, alkylsaccharide excipients can be used in formulations with both hydrophilic and hydrophobic drugs. They are also effective in safely stabilizing protein therapeutics. An example of an alkylsaccharide excipient is dodecyl maltoside (Intravail®; 511 Da, stable long term when stored cold), which provides absorption enhancement by paracellular and transcellular routes. Dodecyl maltoside has been shown to be generally nonirritating to the nose and to promote systemic bioavailability. Dodecyl maltoside is used in US Food and Drug Administration-approved intranasal formulations of sumatriptan for migraine headaches and diazepam nasal spray for patients with epilepsy with acute seizure clusters.


Nasal sprays can offer an easy and efficient route to deliver drugs. The nose can absorb drugs into the bloodstream quickly, and sprays require less patient training than injection or rectal treatments. However, the nasal cavity is small, and the spray must be concentrated and easily absorbed. Alkylsaccharides may enhance absorption in the nose. They have a good safety profile and are used in foods. Intravail® alkylsaccharides include dodecyl maltoside and tetradecyl maltoside. Nasal medications with dodecyl maltoside had drug concentrations and safety similar to injectable forms. Dodecyl maltoside is used in US Food and Drug Administration-approved nasal sprays for migraine (sumatriptan [Tosymra®]) and seizure clusters (diazepam [Valtoco®]). Dodecyl maltoside is also being tested in nasal sprays with other drugs that are absorbed too poorly or slowly on their own. With these new formulations, doctors and patients have more treatment choices and can select the best option.


Assuntos
Excipientes , Preparações Farmacêuticas , Administração Intranasal , Sistema Nervoso Central , Humanos , Mucosa , Estados Unidos
2.
Expert Opin Drug Deliv ; 3(4): 529-39, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16822227

RESUMO

Recent development of a new class of patented alkylsaccharide transmucosal delivery enhancement agents, collectively designated as Intravail (Aegis Therapeutics) absorption enhancers, has created opportunities for new therapeutic options across a broad spectrum of human diseases. Intravail absorption enhancers provide unsurpassed intranasal bioavailabilities, comparable to those that are achieved by injection for protein, peptide and other macromolecular therapeutics. These novel, highly effective and non-irritating excipients circumvent the two primary limitations of intranasal drug delivery, namely mucosal irritation and poor bioavailability, and offer the promise of more convenient, more effective and safer therapeutics for patients and physicians alike. For pharmaceutical companies, Intravail provides a means to capitalise on two important industry dynamics: rapidly growing industry interest in commercialising peptide and protein drugs, and increasing interest in, and use of, the intranasal route for systemic drug delivery.


Assuntos
Desoxiaçúcares , Portadores de Fármacos , Peptídeos/administração & dosagem , Preparações Farmacêuticas/administração & dosagem , Proteínas/administração & dosagem , Administração Intranasal , Adsorção/efeitos dos fármacos , Animais , Disponibilidade Biológica , Desoxiaçúcares/efeitos adversos , Desoxiaçúcares/farmacologia , Portadores de Fármacos/efeitos adversos , Portadores de Fármacos/farmacologia , Humanos , Inaladores Dosimetrados , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Peptídeos/farmacocinética , Proteínas/farmacocinética
3.
Drug Discov Today ; 7(24): 1214-20, 2002 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-12547004

RESUMO

Large-scale comparative analysis of drug-target polymorphism structures enables the rational design of next generation 'super drugs'--drugs that are less prone to development of drug resistance or that work for the largest possible fraction of the patient population. Furthermore, knowledge of the drug-target-shape repertoire that exists within the patient population enables predictions of likely clinical trial outcomes and response rates for drug efficacy. This gives information on the optimal drug candidates before the initiation of clinical trials. The economic impact of incorporating pharmacogenomics insights early on in the drug discovery process will be substantial and will afford significant competitive advantages to companies that successfully incorporate this technology.


Assuntos
Fármacos Anti-HIV/síntese química , Desenho de Fármacos , Farmacorresistência Viral Múltipla , Farmacogenética/métodos , Animais , Farmacorresistência Viral Múltipla/fisiologia , Humanos , Modelos Químicos , Modelos Moleculares
4.
Ther Deliv ; 4(5): 567-72, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23647275

RESUMO

Polysorbates and other polyoxyethylene-based surfactants are incorporated into most biotherapeutics to prevent protein aggregation in order to minimize loss of efficacy, induction of unwanted immunogenicity, altered pharmacokinetics and reduced shelf life. While they are effective in initially preventing protein aggregation, they contain ether linkages (within polyoxyethylene moieties) and in the case of polysorbate 80 unsaturated alkyl chains that spontaneously and rapidly auto-oxidize in aqueous solution to protein-damaging peroxides, epoxy acids and reactive aldehydes, including formaldehyde and acetaldehyde. Oxidative damage induces unwanted immunogenicity and in some instances promotes re-aggregation. Immunogenicity of biotherapeutics is a serious and growing concern for the US FDA and European Medicines Agency and will have significant and growing impact on the development and regulatory approval of both biosimilar and new innovator biotherapeutics.


Assuntos
Carboidratos/química , Fatores Imunológicos/química , Proteínas/química , Tensoativos/química , Animais , Medicamentos Biossimilares/administração & dosagem , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/química , Aprovação de Drogas , Desenho de Fármacos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Oxirredução , Polietilenoglicóis/química , Polissorbatos/química , Proteínas/administração & dosagem , Proteínas/efeitos adversos
5.
Drug Deliv Transl Res ; 3(1): 16-25, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25787864

RESUMO

A new class of alkylsaccharide transmucosal delivery enhancement agents are described that overcome the principal limitations preventing broad acceptance of intranasal administration for many potential applications in systemic drug delivery, namely, poor transmucosal absorption and damage to the nasal mucosa. This review will describe recent developments in use of these excipients in human clinical trials and preclinical studies along with their chemical and pharmacological properties and explore commercial implications of the use of these excipients in introduction of new intranasal formulations of peptidic and nonpeptidic drugs.

6.
Regul Pept ; 167(2-3): 233-8, 2011 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-21329733

RESUMO

The most effective option for the medical treatment of patients with acromegaly is the use of somatostatin analogs. Octreotide acetate is a synthetic analog of somatostatin, with similar effects but a prolonged duration of action. Octreotide acetate is routinely given by subcutaneous (s.c.) or intramuscular injection. In the present study, we examined the feasibility of oral delivery of octreotide acetate reconstituted with increasing concentrations (0.5%, 1.5% and 3.0%) of Intravail®, a patented alkylsaccharide transmucosal absorption enhancing agent. The pharmacokinetics of orally delivered (by gavage) octreotide acetate in Intravail® were compared to those of octreotide acetate administered subcutaneously in sodium acetate buffer to male Swiss Webster mice. Oral delivery of octreotide acetate in 0.5% Intravail® significantly enhanced total uptake (1254.08ng/ml/min vs. 311.63ng/ml/min, respectively), serum half-life (52.1min vs. 1.3min, respectively), and relative bioavailability (4.0 vs. 1.0, respectively) when compared to delivery by s.c. injection. Higher concentrations of Intravail ®did not further enhance uptake, serum half-life, or bioavailability. The results of this study indicate that oral delivery of octreotide acetate in Intravail®is feasible, and is an effective method of administration which significantly improves uptake, bioavailability and half-life when compared to s.c. injection. Thus, oral delivery of octreotide acetate in Intravail® may have significant potential as a novel, non-invasive approach to the treatment of acromegaly and octreotide-mediated symptoms of carcinoid and VIP-secreting tumors.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Monossacarídeos/administração & dosagem , Octreotida/administração & dosagem , Animais , Antineoplásicos Hormonais/farmacocinética , Disponibilidade Biológica , Meia-Vida , Injeções Subcutâneas , Masculino , Taxa de Depuração Metabólica , Camundongos , Octreotida/farmacocinética
7.
J Neuroimmune Pharmacol ; 6(1): 158-62, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20532646

RESUMO

The development of neutralizing antibodies to the protein drug interferon-ß is a significant impediment to its use in the treatment of multiple sclerosis. Neutralizing antibodies to interferon-ß arise from aggregation of the peptide during manufacturing and storage. We tested the ability of dodecylmaltoside, a nontoxic alkylsaccharide surfactant, to reduce aggregation of interferon-ß in vitro and to reduce its immunogenicity in vivo. Interferon-ß, in solution with and without dodecylmaltoside, was periodically evaluated for aggregation by light scatter for 1 month. Interferon-ß, with and without dodecylmaltoside, was given 3 days/week for 1 month to mice; the sera of these mice were analyzed for anti-interferon-ß antibodies by ELISA. Dodecylmaltoside reduces the aggregation of interferon-ß in vitro and its immunogenicity in vivo. Our positive findings warrant additional tests of dodecylmaltoside as a therapeutic adjuvant in rodent models of multiple sclerosis.


Assuntos
Anticorpos Neutralizantes/sangue , Formação de Anticorpos/efeitos dos fármacos , Excipientes/farmacologia , Glucosídeos/farmacologia , Interferon beta/química , Interferon beta/imunologia , Animais , Detergentes/farmacologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interferon beta-1b , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Neopterina/sangue
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